ABSTRACT
Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 µmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings.
Subject(s)
Homocysteine/metabolism , Metabolism, Inborn Errors/diagnosis , Methionine/metabolism , Consensus , Humans , Infant, Newborn , Metabolism, Inborn Errors/metabolism , Methionine Adenosyltransferase/deficiency , Methylation , Neonatal Screening/methods , S-Adenosylhomocysteine/metabolism , S-Adenosylmethionine/metabolismABSTRACT
BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Brain Diseases, Metabolic/diagnosis , Glutaryl-CoA Dehydrogenase/deficiency , Hyperammonemia/diagnosis , Ornithine Carbamoyltransferase Deficiency Disease/diagnosis , Urea Cycle Disorders, Inborn/diagnosis , Adolescent , Adult , Aged , Child , Child, Preschool , Europe , Female , Humans , Infant , Infant, Newborn , Intellectual Disability , Male , Middle Aged , Registries , Vomiting , Young AdultABSTRACT
BACKGROUND: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. METHODS: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. RESULTS: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. CONCLUSIONS: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
Subject(s)
Hyperlysinemias/genetics , Base Sequence , Blotting, Western , Cell Line , Cohort Studies , Comparative Genomic Hybridization , DNA Primers , DNA, Complementary/genetics , Humans , Hyperlysinemias/blood , Hyperlysinemias/physiopathology , Mutation , Saccharopine Dehydrogenases/geneticsABSTRACT
A 4-month-old male infant was brought to the emergency department because of striking petechial skin lesions and acrocyanosis. Routine hematology revealed leukocytosis and thrombocytosis and the infant was admitted for further investigations. Laboratory findings showed no evidence of infection, and a bone marrow aspirate demonstrated a normal number of immature cells of all lineages. Coagulation and routine biochemistry analyses were within the normal range. Three months later, the infant developed signs and symptoms of encephalopathy with episodes of hypotonia and an altered state of consciousness. A brain magnetic resonance imaging suggested the possibility of an inborn error of metabolism. The urinary organic acid and acylcarnitine profile indicated ethylmalonic encephalopathy. Mutation analysis of the ethylmalonic encephalopathy 1 (ETHE1) gene confirmed the diagnosis of ethylmalonic encephalopathy at the molecular level.
Subject(s)
Brain Diseases, Metabolic, Inborn/diagnosis , Leukocytosis/etiology , Purpura/etiology , Thrombocytosis/etiology , Alleles , Atrophy , Brain/pathology , Brain Diseases, Metabolic, Inborn/genetics , Chromosome Deletion , DNA Mutational Analysis , Diagnosis, Differential , Exons/genetics , Fatal Outcome , Humans , Image Interpretation, Computer-Assisted , Infant , Magnetic Resonance Imaging , Male , Malonates/urine , Mitochondrial Proteins/genetics , Nucleocytoplasmic Transport Proteins/genetics , Purpura/diagnosis , Purpura/geneticsABSTRACT
BACKGROUND AND AIM: Citrulline is a non-protein amino acid synthesized in the small intestine. In children with short-bowel syndrome, citrulline has served as a reliable marker of the residual bowel length and parenteral nutrition (PN) independence. In the present study we aim to assess the value of citrulline measurement in preterm neonates developing necrotizing enterocolitis (NEC). METHODS: Plasma citrulline levels were measured prospectively in 17 preterm neonates with NEC stage II during the entire course of the disease. Serial citrulline determinations in 24 healthy preterm neonates on 2, 7, 14, 21 and 28 days of life (DOL), served as reference values. RESULTS: In healthy preterm neonates plasma citrulline levels showed a progressive increase in relation to age. In neonates presenting with NEC, mean citrulline levels were significantly lower as compared to controls' citrulline levels of the most approximate day of life (DOL 7: 16.85±4.2 vs 20.5±4.5 µmol/L, p<0.05; DOL 14: 18±4.2 vs 23.5±4.3 µmol/L, p<0.01; DOL 21: 17±2.5 vs 30±5.7 µmol/L, p<0.01). The optimal citrulline cut-off distinguishing NEC patient from controls was 17.75 µmol/L (sensitivity 76%, specificity 87%). Plasma citrulline at presentation correlated inversely with the duration of parenteral nutrition (r=-0.49, p<0.05). Consecutive citrulline determinations revealed that plasma citrulline increased during reintroduction and gradual increase of enteral nutrition. CONCLUSIONS: Our findings provide preliminary evidence that citrulline levels that are reduced in preterm neonates with NEC in comparison to age-matched controls and serial citrulline determinations could help to monitor improvement of functional enterocyte mass during the course and resolution of NEC.
Subject(s)
Citrulline/blood , Enterocolitis, Necrotizing/blood , Infant, Newborn, Diseases/blood , Infant, Premature/blood , Amino Acids/administration & dosage , Birth Weight/physiology , Case-Control Studies , Enterocolitis, Necrotizing/congenital , Enterocolitis, Necrotizing/diagnosis , Female , Gestational Age , Humans , Infant, Newborn , Male , Parenteral Nutrition , Prognosis , Sensitivity and SpecificityABSTRACT
Deficiency of the sulfide metabolizing protein ETHE1 is the cause of ethylmalonic encephalopathy (EE), an inherited and severe metabolic disorder. To study the molecular effects of EE, we performed a proteomics study on mitochondria from cultured patient fibroblast cells. Samples from six patients were analyzed and revealed seven differentially regulated proteins compared with healthy controls. Two proteins involved in pathways of detoxification and oxidative/reductive stress were underrepresented in EE patient samples: mitochondrial superoxide dismutase (SOD2) and aldehyde dehydrogenase X (ALDH1B). Sulfide:quinone oxidoreductase (SQRDL), which takes part in the same sulfide pathway as ETHE1, was also underrepresented in EE patients. The other differentially regulated proteins were apoptosis inducing factor (AIFM1), lactate dehydrogenase (LDHB), chloride intracellular channel (CLIC4) and dimethylarginine dimethylaminohydrolase 1 (DDAH1). These proteins have been reported to be involved in encephalopathy, energy metabolism, ion transport, and nitric oxide regulation, respectively. Interestingly, oxidoreductase activity was overrepresented among the regulated proteins indicating that redox perturbation plays an important role in the molecular mechanism of EE. This observation may explain the wide range of symptoms associated with the disease, and highlights the potency of the novel gaseous mediator sulfide.
Subject(s)
Gene Expression Regulation/genetics , Mitochondria/metabolism , Proteomics/methods , Aldehyde Dehydrogenase/metabolism , Aldehyde Dehydrogenase 1 Family , Aldehyde Dehydrogenase, Mitochondrial , Amidohydrolases/metabolism , Apoptosis Inducing Factor/metabolism , Brain Diseases, Metabolic, Inborn/metabolism , Cells, Cultured , Chloride Channels/metabolism , Chromatography, Liquid , Fibroblasts/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Oxidation-Reduction , Purpura/metabolism , Skin/cytology , Sulfides/metabolism , Superoxide Dismutase/metabolism , Tandem Mass SpectrometryABSTRACT
OBJECTIVE: Citrulline is a nonprotein amino acid synthesized in the small intestine. The aim of this study is to explore plasma citrulline levels in children with celiac disease (CD) and monitor the time-related changes of these levels after initiation of a gluten-free diet (GFD). METHODS: Fasting-plasma citrulline levels were determined by high-performance liquid chromatography in (i) 23 patients with CD before the institution of GFD, (ii) 20 patients with CD under treatment for more than 2 years responsive to a GFD, (iii) 10 children with gastrointestinal symptoms and normal small bowel biopsy, and (iv) 20 healthy controls. In group A, citrulline levels were also measured after 1, 3, 6, and 12 months on a GFD. RESULTS: Mean plasma citrulline levels were lower in untreated patients with CD (24.5±4.9) than in patients on a GFD (31.2±6.7 µmol/l, P<0.001), patients with gastrointestinal symptoms and normal intestinal mucosa (30.3±4.7 µmol/l, P<0.01), and healthy controls (32.4±7.5 µmol/l, P<0.001). In untreated patients with CD,an inverse correlation was observed between citrulline concentrations and the severity of villous atrophy (r=-0.67, P<0.01). After 1 month on a GFD, patients had significantly higher levels than before diet (P<0.05) and after 3 months on diet, levels were similar to those observed in the healthy controls. CONCLUSIONS: Plasma citrulline levels are lower in celiacs reflecting small bowel involvement in this disease. After a short period on GFD, citrulline levels increased rapidly, indicating that citrulline is a sensitive marker of the positive effect of GFD on intestinal repair.
Subject(s)
Celiac Disease/blood , Celiac Disease/diet therapy , Citrulline/blood , Diet, Gluten-Free , Autoantibodies/blood , Child , Child, Preschool , Female , Humans , Male , Severity of Illness Index , Treatment OutcomeABSTRACT
PURPOSE: To describe the pattern of magnetic resonance (MR) imaging abnormalities in l-2-hydroxyglutaric aciduria (L2HGA) and to evaluate the correlation between imaging abnormalities and disease duration. MATERIALS AND METHODS: MR images in 56 patients (30 male, 26 female; mean age +/- standard deviation, 11.9 years +/- 8.5) with genetically confirmed L2HGA were retrospectively reviewed, with institutional review board approval and waiver of informed consent. At least one complete series of transverse T2-weighted images was available for all patients. The images were evaluated by using a previously established scoring list. The correlation between MR imaging abnormalities and disease duration was assessed (Mann-Whitney or Kruskal-Wallis test). RESULTS: The cerebral white matter (WM) abnormalities preferentially affected the frontal and subcortical regions. The abnormal subcortical WM often had a mildly swollen appearance (37 patients). Initially, the WM abnormalities were at least partially multifocal (32 patients). In patients with longer disease duration, the WM abnormalities became more confluent and spread centripetally, but the periventricular rim remained relatively spared (41 patients). The mean disease duration in patients with WM atrophy (14.8 years) was significantly longer (P = .001) than that in patients without atrophy (6.7 years). Bilateral involvement of the globus pallidus (55 patients), caudate nucleus (56 patients), and putamen (56 patients) was seen at all stages. The cerebellar WM was never affected. The dentate nucleus was involved bilaterally in 55 of 56 patients. CONCLUSION: L2HGA has a distinct highly characteristic pattern of MR imaging abnormalities: a combination of predominantly subcortical cerebral WM abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus. With increasing disease duration, WM abnormalities and basal ganglia signal intensity abnormalities become more diffuse and cerebral WM atrophy ensues.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/metabolism , Glutarates/metabolism , Magnetic Resonance Imaging/methods , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective Studies , Statistics, NonparametricABSTRACT
BACKGROUND: Pearson syndrome is a rare mitochondrial disorder characterized by sideroblastic anemia, liver disease, renal tubulopathy and exocrine pancreas deficiency. OBSERVATIONS: We describe a female infant suffering from anemia since birth who gradually developed the complete picture of Pearson syndrome by 13 months. Iron overload was disproportionate to blood transfusions. The patient was heterozygous for HFE gene C282Y mutation (type I hemochromatosis). After an initial response to deferoxamine she presented with cutaneous zygomycosis and died after metabolic derangement and Pneumocystis jiroveci pneumonia. CONCLUSION: This is the second case of a Pearson syndrome individual who was also heterozygous for HFE gene mutation C282Y published. It is also the second case report of a Pearson patient suffering from severe iron overload and liver disease that responded to therapy with deferoxamine.
Subject(s)
Anemia, Sideroblastic/complications , Hemochromatosis/complications , Histocompatibility Antigens Class I/genetics , Membrane Proteins/genetics , Mitochondrial Diseases/complications , Mutation, Missense , Deferoxamine/therapeutic use , Fatal Outcome , Female , Hemochromatosis Protein , Heterozygote , Humans , Infant , Iron Overload , Liver Diseases , SyndromeABSTRACT
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked defect of purine metabolism. Clinical manifestations are usually related to the degree of enzyme deficiency: complete HPRT deficiency (Lesch-Nyhan syndrome) presenting with severe neurologic or renal symptoms, or partial HPRT deficiency (Kelley-Seegmiller syndrome) manifesting as a gout-urolithiasis syndrome. A 3-generation kindred is described in which the recognition of partial HPRT deficiency in 2 adolescent male siblings presenting with uric acid lithiasis led to the diagnosis in 2 maternal uncles already in renal failure of unknown cause. This report highlights the importance of clinical awareness leading to early diagnosis, appropriate diagnostic methodology, and therapy of a treatable inherited disorder of purine metabolism for the prevention of renal failure.